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Abstract To evaluate the genetics of chronic nonsuppurative otitis media (OM). We performed a genome-wide association study of 429,599 individuals included in the FinnGen study using three different case definitions: combined chronic nonsuppurative OM (7034 cases) (included serous and mucous chronic OM), mucous chronic OM (5953 cases), and secretory chronic OM (1689 cases). Individuals without otitis media were used as controls (417,745 controls). We used immunohistochemistry (IHC) of the murine middle ear to evaluate the expression of annexin A13. Four loci were significantly associated (p

Abstract Background Psychosocial factors and socioeconomic status have been associated with incidence, survival, and quality of life among patients with head and neck cancer. We investigated the association between different psychosocial factors, socioeconomic status, and patient delays in T3–T4 oral, oropharyngeal, and laryngeal cancer. Patients and methods We conducted a nationwide prospective questionnaire-based study (n = 203) over a 3-year period. Results We found no association between psychosocial factors (depression, social isolation, loneliness, and cynical hostility) and patient delay. Depression was three times more common among head and neck cancer patients compared with the general Finnish population. Head and neck cancer patients had lower educational levels and employment status, and were more often current smokers and heavy drinkers. Conclusions Although we found no association between patient delay and psychosocial factors, patients diagnosed with a large head and neck cancer appeared to have a lower socioeconomic status and higher risk for developing depression, which should be considered in clinical practice.

Abstract The increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) is primarily due to human papillomavirus, and understanding the tumor biology caused by the virus is crucial. Our goal was to investigate the proteins present in the serum of patients with OPSCC, which were not previously studied in OPSCC tissue. We examined the difference in expression of these proteins between HPV-positive and -negative tumors and their correlation with clinicopathological parameters and patient survival. The study included 157 formalin-fixed, paraffin-embedded tissue samples and clinicopathological data. Based on the protein levels in the sera of OPSCC patients, we selected 12 proteins and studied their expression in HPV-negative and HPV-positive OPSCC cell lines. LRG1, SDR16C5, PIP4K2C and MVD proteins were selected for immunohistochemical analysis in HPV-positive and -negative OPSCC tissue samples. These protein´s expression levels were compared with clinicopathological parameters and patient survival to investigate their clinical relevance. LRG1 expression was strong in HPV-negative whereas SDR16C5 expression was strong in HPV-positive tumors. Correlation was observed between LRG1, SDR16C5, and PIP4K2C expression and patient survival. High expression of PIP4K2C was found to be an independent prognostic factor for overall survival and expression correlated with HPV-positive tumor status. The data suggest the possible role of LRG1, SDR16C5 and PIP4K2C in OPSCC biology.

Abstract Background Radiotherapy is a core treatment modality for oropharyngeal cancer (OPC), where the primary gross tumor volume (GTVp) is manually segmented with high interobserver variability. This calls for reliable and trustworthy automated tools in clinician workflow. Therefore, accurate uncertainty quantification and its downstream utilization is critical. Methods Here we propose uncertainty-aware deep learning for OPC GTVp segmentation, and illustrate the utility of uncertainty in multiple applications. We examine two Bayesian deep learning (BDL) models and eight uncertainty measures, and utilize a large multi-institute dataset of 292 PET/CT scans to systematically analyze our approach. Results We show that our uncertainty-based approach accurately predicts the quality of the deep learning segmentation in 86.6% of cases, identifies low performance cases for semi-automated correction, and visualizes regions of the scans where the segmentations likely fail. Conclusions Our BDL-based analysis provides a first-step towards more widespread implementation of uncertainty quantification in OPC GTVp segmentation.

Background and purpose: Changes in treatment approaches, characterised by the shift from laryngectomy to a focus on organ-preserving methods may have potentially resulted in lower survival. We aim to identify differences in survival trends for laryngeal cancer (LC) in the Nordic countries over a period of 50 years, and discuss the potential impact of factors such as changes in treatment protocols. Materials and methods: Five-year relative survival (RS) data from 1972 to 2021 were obtained from the NORDCAN database 2.0 which included 33,692 LC cases, of which 85% were diagnosed among men. In the NORDCAN database, the age-standardised RS is calculated using the Pohar Perme estimator with individual International Cancer Survival Standards weights. Joinpoint regression models were used to assess potential shifts in trend over the years in RS. Results: While Denmark and Norway demonstrated an increasing trend in 5-year RS from 1972 to 2021, in Finland and Sweden, the 5-year RS among men remained static, without any discernible significant trend. Over the 30-year period from 1992–1996 to 2017–2021, RS improved by 9, 4, 13, and 2 percentage points in Denmark, Finland, Norway, and Sweden, respectively. Among women in Sweden, a linear negative trend was observed, noticeable as a 16 percentage-point decline in 5-year RS from the earliest to the latest period. Interpretation: The underlying causes for the differences in survival trends remain unclear. Besides differences in treatment protocols, several other factors can affect RS making the interpretation of RS trends challenging.

Abstract Purpose Almost 200,000 tongue cancers were diagnosed worldwide in 2020. The aim of this study was to describe occupational risk variation in this malignancy. Methods The data are based on the Nordic Occupational Cancer (NOCCA) study containing 14.9 million people from the Nordic countries with 9020 tongue cancers diagnosed during 1961–2005. The standardized incidence ratio (SIR) of tongue cancer in each occupational category was calculated using national incidence rates as the reference. Results Among men, the incidence was statistically significantly elevated in waiters (SIR 4.36, 95% confidence interval (CI) 3.13-–5.92), beverage workers (SIR 3.42, 95% CI 2.02-5.40), cooks and stewards (SIR 2.55, 95% CI 1.82-3.48), seamen (SIR 1.66, 95% CI 1.36-2.00), journalists (SIR 1.85, 95% CI 1.18-2.75), artistic workers (SIR 2.05, 95% CI 1.54-2.66), hairdressers (SIR 2.17, 95% CI 1.39-3.22), and economically inactive persons (SIR 1.57, 95% CI 1.42-1.73). Among women, the SIR was statistically significantly elevated only in waitresses (SIR 1.39, 95% CI 1.05-1.81). Statistically significant SIRs ≤ 0.63 were observed in male farmers, gardeners, forestry workers and teachers, and in female launderers. Conclusions These findings may be related to consumption of alcohol and tobacco, but the effect of carcinogenic exposure from work cannot be excluded.

Abstract Background In otosurgical training, cadaveric temporal bones are primarily used to provide a realistic tactile experience. However, using cadaveric temporal bones is challenging due to their limited availability, high cost, and potential for infection. Utilizing current three-dimensional (3D) technologies could overcome the limitations associated with cadaveric bones. This study focused on how a 3D-printed middle ear model can be used in otosurgical training. Methods A cadaveric temporal bone was imaged using microcomputed tomography (micro-CT) to generate a 3D model of the middle ear. The final model was printed from transparent photopolymers using a laser-based 3D printer (vat photopolymerization), yielding a 3D-printed phantom of the external ear canal and middle ear. The feasibility of this phantom for otosurgical training was evaluated through an ossiculoplasty simulation involving ten otosurgeons and ten otolaryngology–head and neck surgery (ORL-HNS) residents. The participants were tasked with drilling, scooping, and placing a 3D-printed partial ossicular replacement prosthesis (PORP). Following the simulation, a questionnaire was used to collect the participants' opinions and feedback. Results A transparent photopolymer was deemed suitable for both the middle ear phantom and PORP. The printing procedure was precise, and the anatomical landmarks were recognizable. Based on the evaluations, the phantom had realistic maneuverability, although the haptic feedback during drilling and scooping received some criticism from ORL-HNS residents. Both otosurgeons and ORL-HNS residents were optimistic about the application of these 3D-printed models as training tools. Conclusions The 3D-printed middle ear phantom and PORP used in this study can be used for low-threshold training in the future. The integration of 3D-printed models in conventional otosurgical training holds significant promise.

Abstract Warthin tumor (WT) is a benign tumor usually affecting the parotid gland. The main diagnostic tool remains ultrasound combined with fine-needle aspiration cytology (FNAC). This study aims to examine how reliably FNAC indicates WT for clinical decision making regarding surgical versus conservative management. We included all patients who underwent FNAC from a parotid gland lesion between 2016 and 2018 at our institution, and whose FNAC revealed WT suspicion. The FNACs were divided into three groups based on the cytology report: certain, likely, and possible WT. The patients were divided into two groups based on having had either surgery or follow-up. We sent a questionnaire to patients who had not undergone surgery in order to obtain follow-up for a minimum of four years. Altogether, 135 FNAC samples, from 133 tumors and 125 patients, showed signs of WT. Of the 125 patients, 44 (35%) underwent surgery, and 81 (65%) were managed conservatively. Preoperative misdiagnosis in FNAC occurred in three (7%) surgically treated tumors. Their FNACs were reported as possible WTs, but histopathology revealed another benign lesion. In the conservatively treated group, two patients underwent surgery later during the follow-up. Cytological statements of WT were seldom false, and none were malignant. The majority of the patients were only followed-up and rarely required further treatment. A certain or likely diagnosis of WT in the FNAC report by an experienced head and neck pathologist is highly reliable in selecting patients for conservative surveillance.

Background The association of chronic sclerosing sialadenitis and IgG4-related disease (IgG4-RD) has resulted in the more frequent identification of IgG4-positivity in submandibular gland inflammations, also uncovering IgG4 overexpression in nonspecific inflammations. These findings lead us to hypothesise that IgG4-positive sialadenitis represents a continuous inflammatory process overlapping histologically with IgG4-RD, possibly differing in aetiology. However, the antigen underlying IgG4 overexpression in IgG4-positive sialadenitis and IgG4-RD remains unknown.Materials and methods Here, we investigated toll-like receptor (TLR) – mediated bacterial inflammation in submandibular gland tissues of patients with IgG4-positive and IgG4-negative chronic inflammatory lesions of the submandibular gland (n = 61), with noninflamed submandibular glands serving as controls (n = 4). Utilising immunohistochemistry, we assessed the expression of TLR2 and TLR4, lipopolysaccharide (LPS) and the P. gingivalis-specific antigen gingipain R1.Results We observed TLR2- and TLR4-immunopositivity in 64 (98%) samples. However, TLR2 and TLR4 staining intensity was significantly stronger in the IgG4-positive group. LPS- and gingipain R1 immunopositivity were observed in 56 (86%) and 58 (89%) samples, respectively. LPS-positivity localised exclusively in mast cell-like cells, while gingipain R1-positivity remained scarce.Conclusions A stronger TLR2 or TLR4 expression in IgG4-positive sialadenitis may indicate a tissue-related factor underlying this form of chronic sialadenitis. LPS- and P. gingivalis immunopositivity remained weak throughout this series. Thus, gram-negative bacteria may not represent pathogens underlying these forms of chronic sialadenitis.

ABSTRACTBackground The etiology behind different types of chronic sialadenitis (CS), some of which exhibit IgG4 overexpression, is unknown. Further, IgG4-related disease (IgG4-RD) commonly affects the submandibular gland, but its relationship to IgG4-overexpressing CS, and the antigen triggering IgG4 overexpression, remain unknown.Materials and Methods By qPCR, we assessed the presence of 21 DNA-viruses causing IgG4 overexpression in submandibular gland tissue from patients with IgG4-positive and IgG4-negative CS. Healthy submandibular glands and glands with sialolithiasis without CS were used as controls. We examined the distribution of HHV-7, HHV-6B and B19V DNA, within virus PCR-positive tissues with RNAscope in-situ hybridization (RISH).Results We detected DNA from seven viruses in 48/61 samples. EBV DNA was more prevalent within the IgG4-positive samples (6/29; 21%) than the IgG4-negative ones (1/19; 5.3%). B19V DNA was more prevalent within the IgG4-negative samples (5/19; 26%) than the IgG4-positive ones (4/29; 14%). The differences in virus prevalence were not statistically significant. Of the IgG4-RD samples (n = 3) one contained HHV-6B DNA. RISH only showed signals of HHV-7.Conclusions None of the studied viruses are implicated as triggering IgG4-overexpression in CS. Although our results do not confirm viral etiology in the examined conditions, they provide valuable information on the prevalence of viruses in both diseased and healthy submandibular gland tissue.

Introduction A better understanding of the earliest stages of Alzheimer’s disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among THL Biobank donors according to TWINGEN study criteria.Methods and analysis A multi-centre study (n=800) to obtain blood-based biomarkers, telephone-administered and web-based memory and cognitive parameters, questionnaire information on lifestyle, health and psychological factors, and accelerometer data for measures of physical activity, sedentary behaviour and sleep. A subcohort is being asked to participate in an in-person neuropsychological assessment (n=200) and wear an Oura ring (n=50). All participants in the TWINGEN study have genome-wide genotyping data and up to 48 years of follow-up data from the population-based older Finnish Twin Cohort (FTC) study of the University of Helsinki. The data collected in TWINGEN will be returned to THL Biobank from where it can later be requested for other biobank studies such as FinnGen that supported TWINGEN.Ethics and dissemination This recall study consists of FTC/THL Biobank/FinnGen participants whose data were acquired in accordance with the Finnish Biobank Act. The recruitment protocols followed the biobank protocols approved by Finnish Medicines Agency. The TWINGEN study plan was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (number 16831/2022). THL Biobank approved the research plan with the permission no: THLBB2022_83.

IntroductionThe effectiveness of the supplementation of prebiotics, probiotics and synbiotics as a therapeutic approach in colorectal cancer (CRC) remains unclear. The aim of this systematic review is to critically examine the current scientific evidence on the impact of modulating the microbiota, through the use of prebiotics, probiotics and synbiotics, in patients diagnosed with CRC undergoing treatment, to determine the potential therapeutic use of this approach.MethodsThis systematic review was made according to the PRISMA 2020 guidelines. Inclusion criteria were randomized controlled trials (RCT) comparing the impact of pre-, pro-, or synbiotic supplementation with placebo or standard care in patients with CRC undergoing treatment. Exclusion criteria were non-human studies, non-RCTs, and studies in languages other than English or Portuguese. Six databases were consulted, namely, Cochrane Library, Pubmed, Scopus, Cinahl, MedicLatina and Web of Science until May of 2023. RAYYAN software was used to manage the search results and risk of bias was assessed according to the guidelines of the Cochrane Collaboration using the Rob 2.0 tool.ResultsTwenty-four RCTs met the inclusion criteria and were included in this review. Administration of pre-, pro-, or synbiotics improved surgical outcomes such as the incidence of infectious and non-infectious postoperative complications, return to normal gut function, hospital length of stay, and antibiotic usage. The supplementation of these microorganisms also alleviated some symptoms from chemotherapy and radiotherapy, mainly diarrhea. Evidence on the best approach in terms of types of strains, dosage and duration of intervention is still scarce.ConclusionsPre-, pro-, and synbiotics supplementation appears to be a beneficial therapeutic approach in CRC treatment to improve surgical outcomes and to alleviate side-effects such as treatment toxicity. More RCTs with larger sample sizes and less heterogeneity are needed to confirm these potential benefits and to determine the best strains, dosage, and duration of administration in each situation.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023413958.

Abstract Protein glycosylation responds sensitively to disease states. It is implicated in every hallmark of cancer and has recently started to be considered as a hallmark itself. Changes in N‐glycosylation microheterogeneity are more dramatic than those of protein expression due to the non‐template nature of protein glycosylation. This enables their potential use in serum‐based diagnostics. Here, we perform glycopeptidomics on serum from patients with oropharyngeal squamous cell carcinoma (OPSCC), compared to controls and comparing between cancers based on etiology (human papilloma virus‐ positive or negative). Using MS2, we then targeted glycoforms, significantly different between the groups, to identify their glycopeptide compositions. Simultaneously we investigate the same serum proteins, comparing whether N‐glycosylation changes reflect protein‐level changes. Significant glycoforms were identified from proteins such as alpha‐1‐antitrypsin (SERPINA1), haptoglobin, and different immunoglobulins. SERPINA1 had glycovariance at 2 N‐glycosylation sites, that were up to 35 times more abundant in even early‐stage OPSCCs, despite minimal differences between SERPINA1 protein levels between groups. Some identified glycoforms' fold changes (FCs) were in line with serum protein level FCs, others were less abundant in early‐stage cancers but with great variance in higher‐stage cancers, such as on immunoglobulin heavy constant gamma 2, despite no change in protein levels. Such findings indicate that glycovariant analysis might be more beneficial than proteomic analysis, which is yet to be fruitful in the search for biomarkers. Highly sensitive glycopeptide changes could potentially be used in the future for cancer screening. Additionally, characterizing the glycopeptide changes in OPSCC is valuable in the search for potential therapeutic targets.

3D printing has been adopted into routine use for certain medical applications, but more widespread usage has been hindered by, among other things, unclear legislation. We performed an analysis, using legal doctrinal study and legal informatics, of relevant EU legislation and case law in four issues relevant to medical 3D printing (excluding bioprinting or pharmacoprinting): pre-market approval, post-market liability, intellectual property rights, and data protection. Several gaps and uncertainties in the current legislation and interpretations were identified. In particular, we regard the current EU regulatory framework to be quite limiting and inflexible, exemplifying a cautionary approach common in EU law. Though the need to establish high safety standards in order to protect patients as a disadvantaged population is understood, both legal uncertainties and overregulation are seen as harmful to innovation. Hence, more adaptive legislation is called for to ensure continuous innovation efforts and enhanced patient outcomes.

Objectives: Adenoid cystic carcinoma (ACC) of the salivary glands has poor long-term prognosis and a high metastatic rate. Toll-like receptors (TLRs), first-line immune activators, have been associated with both tumor progression and suppression. We aimed to study TLR3 and TLR7 behavior in ACC. Materials and methods: We studied TLR3 and TLR7 immunoexpression of 46 minor salivary gland ACCs diagnosed at the Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland over the period 1974–2012. The associations of TLR3 and TLR7 immunoexpression with clinicopathological factors were evaluated by χ2-test and Fisher's exact test. Results: In the majority of samples, both TLR3 and TLR7 were immunoexpressed in cytoplasm. The immunoexpression was heterogeneous between individual tumors. Stronger TLR7 immunoexpression associated with recurrence rate and poorer disease-specific survival (DSS). TLR3 did not associate significantly with survival although we found an inverse correlation between TLR3 and TLR7 immunopositivity. Hence, when TLR3 immunoexpression was negative or mild, TLR7 immunoexpression was moderate to strong, and vice versa. Conclusions: TLR3 and TLR7 are immunoexpressed in minor salivary gland ACC. TLR7 is potentially an independent prognostic marker for recurrence rate and DSS.

Abstract Objective Survival of patients with advanced laryngeal squamous cell carcinoma (LSCC) remains poor and management protocols warrant further development. We thus investigated treatment and outcome‐related factors for LSCC in Stockholm, Sweden. Methods In a retrospective setting, 520 patients with LSCC diagnosed during 2000–2014, were included. Data on stage, treatment, and outcome were correlated with recurrence‐free and overall survival (RFS and OS, respectively). Results Five‐year OS for all patients was 65%. Five‐year RFS for T1a, T1b, T2, T3, and T4 glottic LSCC was 90%, 91%, 77%, 47%, and 80%, respectively. The corresponding figures for T1, T2, T3, and T4 supraglottic LSCC were 64%, 66%, 64%, and 86%. Conclusion Patients with a T3 glottic LSCC had unexpectedly poor survival, especially when compared with patients with a T4 tumor. Patients with T4 disease were primarily treated with laryngectomy and postoperative radiotherapy (RT)/chemoradiotherapy (CRT), while most patients with T3 LSCC were treated with RT/CRT.

Abstract Background Different bacterial infections of the oro-naso-pharyngeal (ONP) region may progress and require hospital care. The present study clarified differences in infection characteristics between hospitalized patients with odontogenic infections (OIs) and other bacterial ONP infections. The specific aim was to evaluate clinical infection variables and infection severity according to infection aetiology, particularly regarding features of OIs compared with other ONPs. Methods Records of patients aged ≥16 years requiring hospital care for an acute bacterial ONP infection in the emergency units of Otorhinolaryngology or Oral and Maxillofacial Surgery at the Helsinki University Hospital (Helsinki, Finland) during 2019 were evaluated retrospectively. The main outcome variables were need for intensive care unit (ICU) treatment and length of hospital stay. The primary predictor variable was infection category, defined as OI or other ONP. The secondary predictor variable was specific ONP infection group. Additional predictor variables were primary clinical infection signs, infection parameters at hospital admission, and delay from beginning of symptoms to hospitalization. Explanatory variables were sex, age, current smoking, heavy alcohol use or substance abuse, and immunosuppressive disease, immunosuppressive medication, or both. Comparison of study groups was performed using Fisher’s exact test, student’s t-test, and Mann-Whitney U. Results A total of 415 patients with bacterial ONPs fulfilled the inclusion criteria. The most common infections were oropharyngeal (including peritonsillar, tonsillar, and parapharyngeal infections; 51%) followed by infections from the odontogenic origin (24%). Clinical features of OIs differed from other ONPs. Restricted mouth opening, skin redness, or facial or neck swelling (or both) were found significantly more often in OIs (p

The shared genetics between upper respiratory diseases have not been well studied. Here, the authors find shared and distinct genetic loci for pharyngeal and sinonasal inflammatory conditions, which show shared heritability with autoimmune conditions and immune deficiency, highlighting the TNFR2 pathway.

Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.

Abstract Background The aim of this study was to estimate occupational risk variation in the incidence of nasopharyngeal cancer (NPC) in a large population-based cohort of the Nordic Occupational Cancer (NOCCA) study. Methods This study is based on a cohort of almost 15 million persons from Denmark, Finland, Iceland, Norway and Sweden, with 2898 nasopharyngeal cancer cases diagnosed in 1961–2005. The data on occupations were gathered from population censuses and cancer data from the national cancer registries. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were estimated using the national NPC incidence rates as the reference. Results There were 1980 male and 918 female NPC patients. The highest SIRs of NPC were observed among male waiters (SIR 3.69, 95% CI 1.91–6.45) and cooks and stewards (SIR 2.24, 95% CI 1.16–3.91). Among women, launderers had the highest SIR of NPC (2.04, 95% CI 1.02–3.65). Significantly decreased SIRs were found among male farmers (SIR 0.79, 95% CI 0.68–0.92) and male textile workers (SIR 0.49, 95% CI 0.22–0.93). Conclusions This study suggests that NPC may be associated with several work-related exposure agents such as smoking, kitchen air pollution and solvents. In future, occupational exposure-risk relations should be studied to understand more about causality and to assess effective prevention strategies.

BackgroundThe mechanisms of Meniere's disease (MD) remain largely unknown. The purpose of this study was to identify possible genetic variants associated with immune regulation in MD.MethodsThe whole immune genome of 16 Chinese patients diagnosed with sporadic MD was sequenced using next-generation sequencing.ResultsDefinite pathological variants of MEFV (c.1223G>A, c.1105C>T), COL7A1 (c.5287C>T), and ADA (c.445C>T) contributing to the clinical phenotype were found in three patients. Limited and likely pathological variants of TLR3 (c.2228G>A) and RAB27A (c.560G>A) were detected in one patient each. The following definite pathological variants impairing the structure and function of translated proteins were detected in 10 patients, and multigene variants occurred in five patients: PRF1 (c.710C>A), UNC13D (c.1228A>C), COLEC11 (c.169C>T), RAG2 (c.200G>C), BLM (c.1937G>T), RNF31 (c.2533G>A), FAT4 (c.11498A>G), PEPD (c.788A>G), TNFSF12 (c.470G>A), VPS13B (c.11972A>T), TNFRSF13B (c.226G>A), ERCC6L2 (c.4613A>G), TLR3 (c.2228G>A), ADA (c.445C>T), PEPD (c.151G>A), and MOGS (c.2470G>A). The following limited pathological variants impairing the structure and function of translated proteins were detected in five patients, with double gene variants identified in one patient: EXTL3 (c.1396G>A), MTHFD1 (c.2057G>A), FANCA (c.2039T>C), LPIN2 (c.1814C>T), NBAS (c.4049T>C), and FCN3 (c.734G>A).ConclusionPatients with sporadic MD carry multiple genetic variants involved in multiple steps of immune regulation, which might render patients susceptible to developing inflammation via both autoimmune and autoinflammation mechanisms upon internal stress.

The effect of head and neck cancer (HNC) radiotherapy (RT) on biomarkers is not known but there is a lot of potential for gaining more precise cancer treatments and less side effects. This cohort study investigated the levels and molecular forms of the matrix metalloproteinase (MMP) -8 and -9, tissue inhibitor of metalloproteinase (TIMP)-1, myeloperoxidase (MPO) and interleukin (IL)-6 in mouth-rinse samples as well as the clinical periodontal status in HNC patients (n = 21) receiving RT. Complete periodontal examinations were performed pre-RT and one month after RT. Mouth-rinse samples (pre-RT, after six weeks of RT and one month after RT) were assayed using a point-of-care-kit (PerioSafe®/ORALyzer® (Dentognostics GmbH, Jena, Germany)) for active MMP-8 and ELISA analysis for total MMP-8 and -9, MPO, TIMP-1, and IL-6 levels. Molecular forms of MMP-9 were assessed by gelatinolytic zymography and MMP-8 by western immunoblot. Significant changes were observed between the three time points in the mean levels of active and total MMP-8, active MMP-9, and IL-6. Their levels increased during the RT and decreased after the RT period. The aMMP-8 levels stayed elevated even one month after RT compared to the pre-RT. Clinical attachment loss, probing depths, and bleeding on probing were increased between pre- and post-calculations in periodontal status. Elevated inflammatory biomarker levels together with clinical recordings strongly suggest that RT eventually increases the risk to the periodontal tissue destruction by inducing the active proteolytical MMP-cascade, and especially by prolonged activity of collagenolytic aMMP-8. Eventually, the aMMP-8 point-of-care mouth-rinse test could be an easy, early detection tool for estimating the risk for periodontal damage by the destructive MMP-cascade in HNC patients with RT treatment.

Bioelectrical Impedance Analysis (BIA) is a reliable, non-invasive, objective, and cost-effective body composition assessment method, with high reproducibility. This scoping review aims to evaluate the current scientific and clinical evidence on BIA for body composition assessment in oncology patients, under active treatment. Literature search was conducted through MEDLINE, CINAHL, Scopus and Web of Science databases, following PRISMA-ScR Guidelines. Inclusion criteria comprised studies reporting the use of BIA for body composition evaluation in adults with cancer diagnosis. Studies including non-cancer pathology or only assessing nutritional status were excluded. This scoping review comprised a total of 36 studies: 25 were original studies including 18 prospective studies, six cross-sectional studies and one retrospective study and 11 were systematic reviews. Population size for the included original articles ranged from 18 to 1217 participants, comprising a total of 3015 patients with cancer with a mean baseline Body Mass Index (BMI) ranging from 20.3 to 30.0 kg/m2 and mean age ranging between 47 and 70 years. Review articles included a total of 273 studies, with a total of 78,350 participants. The current review considered studies reporting patients with head and neck cancer (HNC) (n = 8), breast cancer (BC) (n = 4), esophageal cancer (EC) (n = 2), liver cancer (n = 2), pancreatic cancer (PC) (n = 3), gastric cancer (GC) (n = 3), colorectal cancer (CRC) (n = 8), lung cancer (LC) (n = 1), skin cancer (SK) (n = 1) and multiple cancer types (n = 6). BIA is a suitable and valid method for the assessment of body composition in oncology. BIA-derived measures have shown good potential and relevant clinical value in preoperative risk evaluation, in the reduction of postoperative complications and hospital stay and as an important prognostic indicator in persons with cancer. Future research on the diagnostic value and clinical applications of BIA and BIA-derived phase angle (PhA) should be conducted in order to predict its impact on patient survival and other clinical outcomes.

BackgroundDemand for head and neck cancer (HNC) radiotherapy data in algorithmic development has prompted increased image dataset sharing. Medical images must comply with data protection requirements so that re-use is enabled without disclosing patient identifiers. Defacing, i.e., the removal of facial features from images, is often considered a reasonable compromise between data protection and re-usability for neuroimaging data. While defacing tools have been developed by the neuroimaging community, their acceptability for radiotherapy applications have not been explored. Therefore, this study systematically investigated the impact of available defacing algorithms on HNC organs at risk (OARs).MethodsA publicly available dataset of magnetic resonance imaging scans for 55 HNC patients with eight segmented OARs (bilateral submandibular glands, parotid glands, level II neck lymph nodes, level III neck lymph nodes) was utilized. Eight publicly available defacing algorithms were investigated: afni_refacer, DeepDefacer, defacer, fsl_deface, mask_face, mri_deface, pydeface, and quickshear. Using a subset of scans where defacing succeeded (N=29), a 5-fold cross-validation 3D U-net based OAR auto-segmentation model was utilized to perform two main experiments: 1.) comparing original and defaced data for training when evaluated on original data; 2.) using original data for training and comparing the model evaluation on original and defaced data. Models were primarily assessed using the Dice similarity coefficient (DSC).ResultsMost defacing methods were unable to produce any usable images for evaluation, while mask_face, fsl_deface, and pydeface were unable to remove the face for 29%, 18%, and 24% of subjects, respectively. When using the original data for evaluation, the composite OAR DSC was statistically higher (p ≤ 0.05) for the model trained with the original data with a DSC of 0.760 compared to the mask_face, fsl_deface, and pydeface models with DSCs of 0.742, 0.736, and 0.449, respectively. Moreover, the model trained with original data had decreased performance (p ≤ 0.05) when evaluated on the defaced data with DSCs of 0.673, 0.693, and 0.406 for mask_face, fsl_deface, and pydeface, respectively.ConclusionDefacing algorithms may have a significant impact on HNC OAR auto-segmentation model training and testing. This work highlights the need for further development of HNC-specific image anonymization methods.

Introduction: 3D printing has quickly found many applications in medicine. However, as with any new technology the regulatory landscape is struggling to stay abreast. Unclear legislation or lack of legislation has been suggested as being one hindrance for wide-scale adoption.Methods: A scoping review was performed in PubMed, Web of Science, SCOPUS and Westlaw International to identify articles dealing with legal issues in medical 3D printing.Results: Thirty-four articles fulfilling inclusion criteria were identified in medical/technical databases and fifteen in the legal database. The majority of articles dealt with the USA, while the EU was also prominently represented. Some common unresolved legal issues were identified, among them terminological confusion between custom-made and patient-matched devices, lack of specific legislation for patient-matched products, and the undefined legal role of CAD files both from a liability and from an intellectual property standpoint. Data protection was mentioned only in two papers and seems an underexplored topic.Conclusion: In this scoping review, several relevant articles and several common unresolved legal issues were identified including a need for terminological uniformity in medical 3D printing. The results of this work are planned to inform our own deeper legal analysis of these issues in the future.

AimThis study aimed to determine the prevalence of malnutrition in a head and neck cancer (HNC) population according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and to assess its relation to survival. The secondary aim was to compare GLIM criteria to Patient–Generated Subjective Global Assessment (PG–SGA) and Nutritional Risk Screening 2002 (NRS 2002) methods.MethodsThe assessment was performed in a series of 65 curative patients with newly diagnosed HNC in a nutrition intervention study. Malnutrition was defined as PG-SGA classes BC and nutritional risk as NRS 2002 score ≥3 and was retrospectively diagnosed with GLIM criteria in prospectively collected data at diagnosis. Sensitivity, specificity, and kappa (κ) were analyzed. Predictive accuracy was assessed by calculating the area under curve (AUC) b y receiver operating characteristic (ROC) analysis. Kaplan–Meier and Cox regression analyses were used to evaluate association between malnutrition and overall survival (OS), and disease-free survival (DFS).ResultsGLIM-defined malnutrition was present in 37% (24/65) of patients. The GLIM showed 77% sensitivity and 84% specificity with agreement of κ = 0.60 and accuracy of AUC = 0.80 (p < 0.001) with PG-SGA and slightly higher sensitivity (83%) with NRS 2002 (κ = 0.58). Patients with GLIM-defined malnutrition had shorter OS (56 vs. 72 months, HR 2.26, 95% CI 1.07–4.77, p = 0.034) and DFS (37 vs. 66 months, HR 2.01, 95% CI 0.99–4.09, p = 0.054), than well-nourished patients. The adjusted HR was 2.53 (95% CI 1.14–5.47, p = 0.023) for OS and 2.10 (95% CI 0.98–4.48, p = 0.056) for DFS in patients with GLIM-defined malnutrition.ConclusionA substantial proportion of HNC patients were diagnosed with malnutrition according to the GLIM criteria and this showed a moderate agreement with NRS 2002- and PG–SGA-defined malnutrition. Even though the GLIM criteria had strong association with OS, its diagnostic value was poor. Therefore, the GLIM criteria seem potential for malnutrition diagnostics and outcome prediction in the HNC patient population. Furthermore, NRS 2002 score ≥3 indicates high nutritional risk in this patient group.

Objectives To recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform.Design Biobank-based recontacting pilot study.Setting Three Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021.Participants All eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s).Outcome measures The primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies.Results The overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18–69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92.Conclusion In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.

BackgroundNutritional status in patients with cancer has a determining role in the evolution of the disease and tolerance to treatments. Severity of undernutrition impacts morbidity and mortality in cancer patients and can limit patient response to the optimal therapies if nutritional issues are not appropriately addressed and managed. Despite the importance of malnutrition for the clinical evolution of oncology patients, there is not yet a universally accepted standard method for evaluating malnutrition in such patients. The aim of this study was to stratify the nutritional status of inpatients at an Oncology Department.MethodsThis is an observational study with 561 cancer patients, assessed at admission to a Medical Oncology Department from November 2016 to February 2020. All patients were considered eligible. Non-compliant and/or comatose patients were excluded. Nutritional status was assessed using the PG-SGA, BMI classified with the WHO criteria, and calculation of the percentage of weight loss in the previous 3–6 months.ResultsA total of 561 patients (303 F: 258 M; mean age 65 ± 13 years) were included. One-third of the patients, n=191/561 (34%), lost 6% of their weight in the month prior to admission and 297/561 (53%) patients lost 10.2% of weight in the previous 6 months. Mean BMI was 24.1 ± 5.8 kg/m2; N = 280/561 (50%) patients had regular BMI according to the WHO criteria. N = 331/561 (59%) patients reported eating less in the month prior to admission. N = 303/561 (54%) had moderate/severe deficits of muscle and adipose compartments. The PG-SGA identified 499/561 (89%) patients as moderately/severely malnourished, of which 466/561 (83%) patients scored ≥9 points, meeting criteria for a critical need for nutritional support. Fifteen percent of patients scored >4 points, indicating a need for directed therapy for symptom control and only 1% scored

Abstract Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. Here, we performed a high-throughput compound screen to identify a synergistic interaction between ionizing radiation and 396 anticancer compounds. The assay was run using five human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) cell lines cultured on the human tumor-derived matrix Myogel. Our screen identified several compounds with strong synergistic and antagonistic effects, which we further investigated using multiple irradiation doses. Navitoclax, which emerged as the most promising radiosensitizer, exhibited synergy with irradiation regardless of the p53 mutation status in all 13 HNSCC cell lines. We performed a live cell apoptosis assay for two representative HNSCC cell lines to examine the effects of navitoclax and irradiation. As a single agent, navitoclax reduced proliferation and induced apoptosis in a dose-dependent manner, whereas the navitoclax–irradiation combination arrested cell cycle progression and resulted in substantially elevated apoptosis. Overall, we demonstrated that combining navitoclax with irradiation resulted in synergistic in vitro antitumor effects in HNSCC cell lines, possibly indicating the therapeutic potential for HNSCC patients.

Abstract Background The aim was to evaluate the relative proportion of Non‐steroidal anti‐inflammatory drug exacerbated respiratory disease (NERD) and other comorbidities, and their impact on the burden of outpatient visits due to allergic rhinitis (AR), non‐allergic rhinitis (NAR), acute rhinosinusitis (ARS), and chronic rhinosinusitis with nasal polyps (CRSwNP) and without (CRSsNP). Methods We used hospital registry data of a random sample of 5080 rhinitis/rhinosinusitis patients diagnosed during 2005–2019. International Statistical Classification of Diseases and Related Health Problems (ICD10) diagnoses, visits, and other factors were collected from electronic health records by using information extraction and data processing methods. Cox's proportional hazards model was used for modeling the time to the next outpatient visit. Results The mean (±standard deviation) age of the population was 33.6 (±20.7) years and 56.1% were female. The relative proportion of AR, NAR, ARS, CRSsNP and CRSwNP, were 33.5%, 27.5%, 27.2%, 20.7%, and 10.9%, respectively. The most common other comorbidities were asthma (44.4%), other chronic respiratory diseases (38.5%), musculoskeletal diseases (38.4%), and cardiovascular diseases (35.7%). Non‐steroidal anti‐inflammatory drug exacerbated respiratory disease existed in 3.9% of all patients, and 17.7% of the CRSwNP group. The relative proportion of subjects having 1, 2, 3 and ≥ 4 other diseases were 18.0%, 17.6%, 17.0%, 37.0%, respectively. All diseases except AR, ARS, and mouth breathing, were associated with a high frequency of outpatient visits. Conclusions Our results revealed a high relative proportion of NERD and other comorbidities, which affect the burden of outpatient visits and hence confirm the socioeconomic impact of upper airway diseases.

Abstract Background Obstructive sleep apnea (OSA) is prevalent in individuals with Osteogenesis imperfecta (OI). To date, no study has investigated treatment of OSA in adult individuals with OI using positive airway pressure (PAP). This observational pilot study examined the adherence of adults with OI to treatment of OSA with PAP therapy, and the evolution of self-experienced sleepiness and depression symptoms before and after treatment. Methods We included 20 patients, with a mean age of 51 years, who represented varying severity of OI and displayed an apnea and hypopnea index ≥ 5 /sleeping hour as recorded by an overnight polysomnography. PAP therapy was proposed to all patients. Epworth Sleepiness Scale (ESS) questionnaire to evaluate daytime sleepiness, and a validated self-rating depression questionnaire to identify possible depression, were completed prior to PAP therapy and repeated after a minimum of one year. The datasets supporting the conclusions of this article are included within the article. Results From the 20 patients, 15 initiated PAP therapy, and two patients later interrupted it. The mean PAP follow-up period was 1230 days. At baseline, an abnormally high ESS score was reported by 29% of the respondents, and an abnormally high number of symptoms suggesting depression by 29%. Follow-up questionnaires were completed by 60% of the patients, of whom 83% were adherent to PAP treatment. ESS score and depression symptoms did not decrease significantly with PAP therapy. Conclusions Patients with OI accepted well PAP therapy and remained compliant. Sleepiness and depression persisted unaltered despite good PAP adherence. These unexpectedly poor improvements in symptoms by PAP therapy may be due to subjective depression symptoms and the complexity of factors underlying persisting sleepiness in OI. Further research is needed to confirm this novel finding.

AbstractBackground Early diagnosis of head and neck cancer (HNC) will improve patient outcomes. The low incidence of HNC renders its detection challenging for a general practitioner (GP) in primary health care (PHC).Patients and methods To examine these challenges, our cohort consisted of all patients visiting PHC centres in the City of Helsinki in 2016. We chose 57 ICD-10 codes representing a sign or symptom resulting from a possible HNC and compared data for all new HNC patients.Results A total of 242,211 patients (499,542 appointments) visited PHC centres, 11,896 (5%) of whom presented with a sign or symptom possibly caused by HNC. Altogether, 111 new HNCs were diagnosed within the Helsinki area, of which 40 (36%) were referred from PHC. The median delay from the initial PHC visit to the referral to specialist care was 5 days, whereby 88% of patients were referred within one month.Conclusions Despite the low incidence of HNC and the large number of patients presenting with HNC-related symptoms, GPs working in PHC sort out potential HNC patients from the general patient group in most cases remarkably effectively.KEY MESSAGESFor every head and neck cancer (HNC) patient encountered in the primary health care, a general practitioner (GP) will meet approximately 6000 other patients, 100 of whom exhibit a sign or a symptom potentially caused by a HNC.Despite the low incidence of HNC, GPs referred patients to specialist care effectively, limiting the median delay from the initial appointment to referral to only 5 days.

ObjectivesTo integrate mRNA and miRNA expression profiles of mucoepidermoid carcinomas (MECs) and normal salivary gland (NSGs) tissue samples and identify potential drivers.Material and MethodsGene and miRNA expression arrays were performed in 35 MECs and six NSGs.ResultsWe found 46 differentially expressed (DE) miRNAs and 3,162 DE mRNAs. Supervised hierarchical clustering analysis of the DE transcripts revealed two clusters in both miRNA and mRNA profiles, which distinguished MEC from NSG samples. The integrative miRNA-mRNA analysis revealed a network comprising 696 negatively correlated interactions (44 miRNAs and 444 mRNAs) involving cell signaling, cell cycle, and cancer-related pathways. Increased expression levels of miR-205-5p and miR-224-5p and decreased expression levels of miR-139-3p, miR-145-3p, miR-148a-3p, miR-186-5p, miR-338-3p, miR-363-3p, and miR-4324 were significantly related to worse overall survival in MEC patients. Two overexpressed miRNAs in MEC (miR-22 and miR-205) were selected for inhibition by the CRISPR-Cas9 method. Cell viability, migration, and invasion assays were performed using an intermediate grade MEC cell line. Knockout of miR-205 reduced cell viability and enhanced ZEB2 expression, while miR-22 knockout reduced cell migration and invasion and enhanced ESR1 expression. Our results indicate a distinct transcriptomic profile of MEC compared to NSG, and the integrative analysis highlighted miRNA-mRNA interactions involving cancer-related pathways, including PTEN and PI3K/AKT.ConclusionThe in vitro functional studies revealed that miR-22 and miR-205 deficiencies reduced the viability, migration, and invasion of the MEC cells suggesting they are potential oncogenic drivers in MEC.

Abstract Background The nature of parotid tumors often remains unknown preoperatively and final histopathology may reveal unexpected malignancy. Still, the use of fine‐needle aspiration cytology (FNAC) and imaging varies in the management of these tumors. Methods We evaluated the preoperative examinations and management of all 195 parotid gland tumors diagnosed within our catchment area of 1.6 million people during 2015. Results Altogether 171 (88%) tumors were classified as true salivary gland neoplasms. FNAC showed no false malignant findings, but it was false benign in 5 (2.6%) cases. Preoperative MRI was utilized in 48 patients (25%). Twenty (10%) malignancies included 16 salivary gland carcinomas. Pleomorphic adenomas accounted for 52% of all adenomas. For 24 (40%) Warthin tumors, surgery was omitted. Conclusion The proportion of malignancies was lower than generally presented. Our proposed guidelines include ultrasound‐guided FNAC with certain limitations. MRI is warranted in selected cases, but seems unnecessary routinely.

Abstract Background The incidence of human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Patients with HPV-associated and HPV-unassociated OPSCC differ in many aspects, which may also impact their diagnostic and management timelines. This study aims at studying the patient, primary health care (PHC) and specialist-care (SC) delays and possible differences between these two patient groups in seeking medical care. Methods We reviewed all new patients with OPSCC treated between 2016 and 2018 at our institute, which covers a referral area of 1.6 million people. We collected data on patients’ symptoms and factors influencing why they sought medical care using a patient-reported questionnaire and hospital records. We compared delays based on patient and tumor characteristics. Results In our study population of 83 patients, the median patient delay was 30 days (range, 0–366), with a median PHC delay of 15 days (range, 0 days–2.5 years), and a median SC delay of 54 days (range, 12–231). The SC delay was further divided into diagnostic hospital delay and treatment delay, each with a median length of 16 days (range, 0–237) and 29 days (range, 0–73), respectively. Furthermore, we found that p16 status did not associate with delays. A longer patient delay associated with specific tumor factors, such as a larger primary tumor and a lower UICC 7th edition stage. Patients that had multiple visits or did not have a follow-up visit scheduled at the initial appointment had longer PHC delays. Treatment delay was significantly longer for patients scheduled for (chemo-)radiotherapy than for those undergoing surgery with or without (chemo-)radiotherapy. Conclusions Although delays remained short for the majority of OPSCC patients, long delays require further evaluation and improvement of management. Awareness of presenting symptoms among cancer risk patients and prompt referral practice or a follow-up visit at PHC represent key factors to shortening these delays. Ultimately, the causes for delays in SC appear multifactorial and require institutional quality control.

BackgroundHuman papilloma virus is associated with oral and oropharyngeal cancer. Our aim was to examine oral health in patients with oropharyngeal (OPSCC) and oral tongue cancer (OTSCC), expecting better oral health among OPSCC patients.Material and methodsFifty-five OPSCC patients with known HPV status and 59 OTSCC patients were randomly selected from a list of consecutive patients of the Helsinki University Hospital, Finland. Oral health was assessed from panoramic jaw radiographs. Total Dental Index (TDI) summarizing the dental health status was calculated and Finnish population study data were used for comparison. Descriptive statistics were used for analyses.ResultsPatients with HPV-positive OPSCC had higher periapical lesion index compared with HPV-negative OPSCC patients or with OTSCC patients. Residual roots were more common among OPSCC patients compared with OTSCC patients, because of their higher occurrence among HPV-negative OPSCC patients compared with OTSCC patients. Similarly, modified TDI score was significantly higher among OPSCC patients than among OTSCC patients, because of higher TDI score among HPV-negative OPSCC patients compared with OTSCC patients. OPSCC patients more often used a removable prosthesis than OTSCC patients. Dental health of the cancer patients was poorer when compared with the population data.ConclusionsOur study hypothesis was only partly confirmed. Periapical lesions were more prevalent among HPV-positive OPSCC patients, compared with the other groups. The number of residual roots was higher among HPV-negative subgroup. Thus, OPSCC patients had worse oral health parameters than OTSCC patients.

Objective Reports on sinonasal oncocytic papilloma (SNOP) are scarce. The aim of this retrospective study was to evaluate the clinical features of this rarest form of sinonasal papilloma with special emphasis on the pattern of recurrences and on the potential factors predicting them. Study Design Retrospective study. Methods Between the years 1994 and 2016, 20 patients (mean age 66 years; range 30–87) were diagnosed with SNOP at the Department of Otorhinolaryngology–Head and Neck Surgery, HUS Helsinki University Hospital (Helsinki, Finland). Hospital charts were reviewed to record various medical and sociodemographic patient characteristics, and the archived histological specimens were re‐evaluated. Postoperative follow‐up time varied between 26 days and 167 months. Results Maxillary sinus was the most common (60%) tumor location. None of the tissue samples showed dysplasia. Recurrence rate was 39% and the median time span to the first recurrence was 25 months (range 7–71). Smokers had more often a recurrence than nonsmokers (75% vs. 31%). Patients with perioperative purulent rhinosinusitis during the primary surgery had a higher recurrence rate compared with those without (60% vs. 31%). Tumors located in the sinuses recurred more often than those located in the nasal cavity (45% vs. 29%). However, all these findings remained statistically nonsignificant. None of the cases showed malignant transformation during the follow‐up. Conclusion SNOP has a propensity to recur. History of smoking, purulent rhinosinusitis during the primary surgery, and tumor location in the sinuses outside the nasal cavity seem to contribute to an increased trend in the risk of recurrence. Level of Evidence 4

IntroductionLung cancer (LC) is highly prevalent worldwide, with elevated mortality. In this population, taste and smell alterations (TSAs) are frequent but overlooked symptoms. The absence of effective therapeutic strategies and evidence-based guidelines constrain TSAs’ early recognition, prevention and treatment (Tx), promoting cancer-related malnutrition and jeopardizing survival outcomes and quality of life.ObjectivesTo systematically review the literature on TSAs in LC patients, understand the physiopathology, identify potential preventive and Tx strategies and to further encourage research in this area.MethodsLiterature search on English language articles indexed to PubMed, CINALH, SCOPUS and Web of Science using MeSH terms “Lung neoplasms”,”Dysgeusia”, “Olfaction Disorders”, “Carcinoma, Small Cell”,”Carcinoma, Non- Small-Cell Lung “Adenocarcinoma of Lung”,”Carcinoma, Large Cell”, and non-MeSH terms “Parageusia”, “Altered Taste”, “Smell Disorder”, “Paraosmia”, “Dysosmia”,”Lung Cancer” and “Oat Cell Carcinoma”.ResultsThirty-four articles were reviewed. TSAs may follow the diagnosis of LC or develop during cancer Tx. The estimated prevalence of self-reported dysgeusia is 35-38% in treatment-naïve LC patients, and 35-69% in those undergoing Tx, based on studies involving LC patients only.One prospective pilot trial and 1 RCT demonstrated a clinically significant benefit in combining flavor enhancement, smell and taste training and individualized nutritional counselling; a systematic review, 1 RCT and 1 retrospective study favored using intravenous or oral zinc-based solutions (150mg 2-3 times a day) for the prevention and Tx of chemotherapy (CT) and radiotherapy (RT) -induced mucositis and subsequent dysgeusia.ConclusionsThis is the first review on dysgeusia and dysosmia in LC patients to our knowledge. We propose combining taste and smell training, personalized dietary counselling and flavor enhancement with oral zinc-based solutions (150mg, 2-3 times a day) during CT and/or RT in this population, in order to prevent and help ameliorate Tx-induced dysgeusia and mucositis. However due to study heterogeneity, the results should be interpreted with caution. Developing standardized TSA measurement tools and performing prospective randomized controlled trials to evaluate their effect are warranted.

Thermal and chemical ablation are minimally invasive procedures that avoid removal of the thyroid gland and target symptomatic nodules directly. Internationally, Radiofrequency ablation (RFA) is among one of the most widely used thermal ablative techniques, and is gaining traction in North America. Surgery remains the standard of care for most thyroid cancer, and in the right clinical setting, Active Surveillance (AS) can be a reasonable option for low risk disease. Minimally invasive techniques have emerged as an alternative option for patients deemed high risk for surgery, or for those patients who wish to receive a more active treatment approach compared to AS. Herein, we review the literature on the safety and efficacy of RFA for treating benign non-functioning thyroid nodules, autonomously functioning thyroid nodules, primary small low risk thyroid cancer (namely papillary thyroid cancer) as well as recurrent thyroid cancer.

Abstract Background Currently, in vivo model for personalised cancer drug testing is challenging. A zebrafish larvae xenograft model has been applied in recent years to cancer research, particularly for drug testing purposes, showing promising results in drug testing against patient-derived tumour xenografts. Currently, these xenograft models apply imaging techniques to measure drug efficacy. However, this method carries several limitations, including timely imaging, thereby reducing the available number of tested fish and drugs. Here, we propose a PCR-based fast assay to evaluate drug efficacy in a zebrafish larvae xenograft model. Methods We tested two primary and corresponding metastatic head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived tongue cancer sample applying zebrafish larvae xenograft model. Cisplatin efficacy was tested using imaging technique and compared the results with PCR-based methods. Drug screening of eight compounds was applied on both cell lines and patient sample using PCR. Results In a head-to-head comparison, all the three techniques (imaging, quantitative PCR, and droplet digital PCR) showed similar reduction of the cancer cells growth after cisplatin treatment. Using the quantitative PCR assay, we demonstrated a dose-dependent response of HNSCC cells to cisplatin. Drug screening results of four HNSCC cell lines and patient sample revealed different drug efficacy between tested cancer cells. Conclusion We introduce a novel, easy, fast and cost-effective PCR-based in vivo zebrafish larvae assay to test the response of cell lines and clinical tumour samples to anti-cancer drugs. This method goes hand-by-hand with the commonly used imaging assay.

Most SARS CoV-2 infections probably occur unnoticed or cause only cause a mild common cold that does not require medical intervention. A significant proportion of more severe cases is characterized by early neurological symptoms such as headache, fatigue, and impaired consciousness, including respiratory distress. These symptoms suggest hypoxia, specifically affecting the brain. The condition is best explained by primary replication of the virus in the nasal respiratory and/or the olfactory epithelia, followed by an invasion of the virus into the central nervous system, including the respiratory centers, either along a transneural route, through disruption of the blood-brain barrier, or both. In patients, presenting with early dyspnea, the primary goal of therapy should be the reversal of brain hypoxia as efficiently as possible. The first approach should be intermittent treatment with 100% oxygen using a tight oronasal mask or a hood. If this does not help within a few hours, an enclosure is needed to increase the ambient pressure. This management approach is well established in the hypoxia-related diseases in diving and aerospace medicine and preserves the patient’s spontaneous breathing. Preliminary research evidence indicates that even a small elevation of the ambient pressure might be lifesaving. Other neurological symptoms, presenting particularly in long COVID-19, suggest imbalance of the autonomous nervous system, i.e., dysautonomia. These patients could benefit from vagal nerve stimulation.

Abstract Background Patients with Osteogenesis imperfecta (OI) suffer from increased bone fracture tendency generally caused by a mutation in genes coding for type I collagen. OI is also characterized by numerous co-morbidities, and recent data from questionnaire studies suggest that these may include increased risk for sleep apnea, a finding that lacks clinical evidence from cohort studies. In this cross-sectional study, 25 adults with OI underwent clinical otorhinolaryngology examination as well as overnight polysomnography to address the question. The participants were aged between 19 and 77 years, and ten of them had mild clinical OI phenotype, seven had a moderately severe phenotype, and eight had a severe phenotype. Results We found obstructive sleep apnea (apnea hypopnea index ≥5/h) in as many as 52% of the OI patients in the cohort. Unexpectedly, however, no correlation was present between sleep apnea and daytime sleepiness, experienced bodily pain, severity of OI, Mallampati score, or neck circumference. Conclusions Seeing that the usual predictors showed no association with occurrence of sleep apnea, we conclude that obstructive sleep apnea may easily be left as an undetected disorder in individuals with OI. Recurrent nocturnal hypoxia due to episodes of apneas can even affect bone metabolism, thereby further aggravating bone fragility in patients with OI.

Abstract Background Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete. Results We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17 years, and healthy age-matched controls. The proportion of B cells (CD19+) and naïve B cells (CD27−, IgD+) were high while memory B cells (CD27+) and switched memory B cells (CD27+IgM−IgD−), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21low, CD38low) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4+ T cells was reduced significantly and the proportion of CD8+ T central memory significantly elevated. An increased proportion of CD57+ CD8+ T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16+ and CD27− NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity. The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L+ T cells, naïve CD4+ and CD27+ CD8+ T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8+ cells and decreased the proportion of activated B cells and plasmablasts in three patients studied. Conclusions This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.